Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Dhiraj Acharya, University of Southern Mississippi
Penghua Wang, Yale University
Amber M. Paul, University of Southern Mississippi
Jianfeng Dai, Yale University
David Gate, University of Southern California
Jordan E. Lowery, University of Southern Mississippi
Dobrivoje S. Stokic, Methodist Rehabilitation Center, Jackson
A. Arturo Leis, Methodist Rehabilitation Center, Jackson
Richard A. Flavell, Yale University
Terrence Town, University of Southern California
Erol Fikrig, Yale University
Fengwei Bai, University of Southern Mississippi

Abstract

CD8⁺ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8⁺ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a^−/−) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8⁺ T cells isolated from Il17a^−/− mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8⁺ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.

IMPORTANCE Interleukin-17A (IL-17A) and CD8⁺ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8⁺ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8⁺ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8⁺ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A–CD8⁺ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8⁺ T cell functions are crucial.